Natural variation in population of Plasmodium falciparum may seriously complicate efforts to develop malaria vaccine. Whether single stage of multivariant, if a portion of the parasite population can escape the effects of a vaccine because of heritable variation in vaccine-target antigen, the natural parasite population could evolve 'vaccine resistance' in a manner analogous to the development of drug resistant. Such evolution will be far less likely against a vaccine capable of inducing protective immunity with several of its polymorphic components. With sufficient levels of such redundancy, the probability of encountering a parasite with the appropriate combination of non- recognized target antigen could become vanishingly small. Thus, study of natural variation in parasite antigens that are to be considered as potential components of a malaria vaccine is essential. Based on experience with the CS proteins of P. falciparum and P. vivax, it has observed that polymorphism in the malarial proteins is mostly restricted to the epitopes that interface with the various arms of the host immune system, possibly allowing the parasites to evade host immune pressures. The goals of this proposed study are to, first, determine the extent and nature of variation in the three P. falciparum vaccine candidate antigens, which are, the CS, MSP-1, and Pfs 25kd antigen, second, determine immunologic implication of polymorphisms in the CTL activity of the polymorphic CTL determinant of the CS protein, identify T-helper and T-proliferative sites in the MSP-1 molecule, and evaluate immunologic implication of polymorphism. We will use parasites from two malarious region, Kenya and Brazil. In the case of parasites from Kenya, the genes encoding the parasite antigens will be characterized from individuals of different ages in a longitudinal study. The studies of T-cell proliferations and CTL activity will be conducted in rodent model system and in humans. The information on the extent, nature, and immunologic relevance of epitope polymorphism together with available clinical and epidemiologic data is essential for both vaccine designs and field testing of malaria vaccines.